To better understand how transposable elements (TEs) cause disease, we need to understand how they are controlled in human cells. There is a gap in the knowledge of small RNAs and proteins involved in the TE silencing pathways in humans. The long- term goal is to understand how the genome is protected against the mutagenesis of TEs. The objective of this study is to identify small RNAs and proteins functioning in TE silencing in three separate stages of the TE life cycle. We hypothesize that 1) endogenous siRNAs and TE-derived miRNAs function in TE silencing by guiding TE DNA methylation and TE transcript degradation; and 2) somatic mutations are responsible for the activation of transposable elements in TE de-repressed cells. To test these hypotheses, we will utilize the cancer samples as the model for TE de-repression. Using bioinformatics, we can extract TE-derived small RNAs, methylation of TE promoters, TE transcript levels, and de-novo TE insertions from the Cancer Genome Atlas data. Using these variables on TEs, we will identify small RNAs and genes involved in TE silencing. For aim 1, we will test each small RNA for significant correlation with methylation and transcript levels across TE de-repressed samples. For aim 2, we will test each locus harboring somatic mutations for association with variation in TE activity in de-repressed cells. The approach is innovative, since it allows access to thousands of natural experiments with variation in TE activity. The availability of cancer-normal pairs allows a genome-wide associate study approach that was not possible before with typical population genomic data. The outcomes from this work will be a list of candidate loci that function in TE silencing in human somatic cells, and a global picture of the model for TE silencing in humans. The proposed research is significant because it will advance our knowledge on the molecular details of TE silencing in human somatic cells. This knowledge will ultimately increase our understanding of mutations caused by TEs, and why TEs are de-repressed in certain diseases.